This application is related to U.S. Ser. No. 07/694,321 (abandoned); U.S. Ser. No. 07/694,157, now U.S. Pat. No. 5,240,693; and U.S. Ser. No. 07/694,151, now U.S. Pat. No. 5,399,338; all entirely incorporated by reference herein.
One of the most difficult problems in in vivo imaging of living organisms is how to distinguish between normal and aberrant tissue. Many approaches to this problem have been developed, including inter alia, X-ray imaging (including CAT-scanning), radionuclide imaging, fluoroscopy, ultrasonic imaging and nuclear magnetic resonance (NMR) imaging (MRI), with and without the administration of imaging agents, e.g., contrast media. The imaging agent may comprise materials which are themselves opaque to the detection signal and simply increase the contrast between organs or tissues containing it and organs or tissues which do not, e.g., as with X-ray agents. Alternatively, the agent can be one which has a local effect on the endogenous moiety active to the modality, as in the effect of NMR contrast agents on protons in vivo. For example, such agents may comprise materials which are selectively biodistributed due to pharmacokinetics or affinity for a certain compound, cell type, tissue, organ, etc. In the latter case, the agent will highlight those areas containing the matter for which the agent has affinity; in the former, it will highlight the areas where it is selectively transported. Many such imaging agents are well known in the relevant arts, as are methods of use thereof.
Each of the known agents and methods suffers from a variety of deficiencies related to tolerability of the imaging agent, invasive nature of the active radiation and efficiency and accuracy of the diagnosis enabled by the resulting image. For example, NMR imaging is the most safe in terms of the radiation used. It does not involve ionizing radiation as does X-ray. Under many circumstances it provides very detailed information by imaging of various tissues. However, it suffers from a limitation based upon the lack of distinction between normal and aberrant tissue which has the same NMR signature. Although several approaches have been taken toward increasing the specificity of NMR contrast agents (usually involving paramagnetic compounds, often in combination with targeting agents, e.g., antibodies), these are limited in that they rely on administration of materials, e.g., antibodies, whose in vivo specificity must be determined in advance of application. The known NMR contrast agents, such as, e.g., gadolinium-DTPA, are not universally specific for all abnormal vs. normal tissue. What is needed is a contrast agent which is specific for aberrant tissue vs. its normal tissue counterpart, to as universal an extent as possible, and which can correspondingly be used substantially non-specifically, i.e., as universally as possible, to locate and diagnose aberrant tissues in a large proportion of the body of a living organism.
The present invention provides methods of imaging comprising administering an imaging-effective amount of a biomodulator, e.g., of enhancing the contrast of an NMR image of abnormal tissue of a host, comprising administration to a host of an amount of a biomodulator effective to enhance said contrast, e.g., wherein abnormal tissue of the host has enhanced contrast.
In a more general aspect, this invention provides a method of imaging tissue, preferably abnormal tissue, comprising administering a biomodulator, optionally labelled with a moiety detectable by a selected imaging modality, or optionally administered in conjunction with an imaging-active agent whose biodistribution is changed by the administration of a biomodulator, in an amount effective to image the tissue.
For MRI, as indicated above, no label is necessary. The biomodulators of this invention selectively biodistribute in certain tissue whereby they modify the distribution of water (protons detectable by MRI) in the local environment, thereby producing an image of the environment which is different from that of the environment without biomodulator mediation. This difference alone will provide diagnostically useful information in MRI.
In another aspect, this invention provides a method of delivering a drug to a particular site in a body of a host containing abnormal tissue comprising administering a biomodulator and said drug, the amounts of said biomodulator and said drug being effective to selectively concentrate said drug at said site of abnormal tissue.